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PURPOSE: We evaluated the oncologic efficacy of early inguinal lymph-node dissection, observation or dynamic sentinel node biopsy followed by delayed or selective inguinal lymph-node dissection in cN0 patients with penile squamous cell carcinoma. MATERIALS AND METHODS: Between 1980 and 2017 (inclusive), 296 evaluable consecutive cN0 penile squamous cell carcinoma patients underwent early inguinal lymph-node dissection (16), observation (114) or dynamic sentinel node biopsy (166). Median followup was 50 months. Tumor stage, grade, lympho-vascular invasion and age were considered. Kaplan-Meier plots illustrated 5-year inguinal relapse-free and cancer specific survival rates. Multivariable Cox regression models tested the treatment effect. Analyses were repeated after inverse probability of treatment weighting adjustment. RESULTS: The 5-year inguinal relapse-free survival and cancer specific survival rates following early, observation and dynamic sentinel node biopsy inguinal lymph-node dissection were 100%, 87%, 89%, and 84%, 81%, 85%, respectively. The 5-year crude inguinal relapse-free survival and cancer specific survival rates were 90% and 93% in low-risk patients undergoing observation. Clavien grade 3 complications were 0.6 vs 12.5% in the dynamic sentinel node biopsy and early inguinal lymph-node dissection group, respectively. After inverse probability after treatment weighting adjustment, 5-year inguinal relapse and cancer specific survival were 90% vs 73% and 90% vs 77% following dynamic sentinel node biopsy and observation, respectively. At multivariable Cox regression model, patients undergoing dynamic sentinel node biopsy had significantly lower inguinal relapse (HR 0.4, 95% CI 0.2-0.85, p 0.02) and cancer specific mortality (HR 0.29, 95% CI 0.11-0.77; p=0.01) compared to those under observation. The low number of patients undergoing early inguinal lymph-node dissection made a reliable comparison with this group impractical. CONCLUSIONS: Selective inguinal lymph-node dissection following dynamic sentinel node biopsy significantly improved inguinal relapse and cancer specific mortality when compared with observation, providing evidence of efficacy of dynamic sentinel node biopsy in clinical stage N0 squamous cell carcinoma of the penis.

Renal tumor biopsy was provided in patients candidate to radical nephrectomy for a renal mass ≥4 cm, to evaluate treatment deviation.Between 2008 and 2017, 102 patients with a solid renal mass ≥4 cm with no distant metastases underwent preliminary renal tumor biopsy. We investigated the proportion of patients who proceeded with radical nephrectomy, variables predicting non-renal cell carcinoma (RCC) and concordance between biopsy findings and definitive pathology.Median tumor size was 70 mm (IQR 55-110). Clinical stage was cT1b in 41, cT2 in 33, cT3 in 25 and cT4 in three patients. A median of three (IQR 2-3) renal tumor biopsies were taken with 16/18 Gauge needles in 97% of cases. Clavien grade I complications occurred in five cases. Malignant tumors were documented in 84 patients: 78 RCCs and six non-RCCs. Fifteen biopsies documented oncocytoma and three were non-diagnostic. Grade was reported in 50 RCCs: 42 (84%) were low and eight (16%) high grade. Eighty-three patients proceeded with radical nephrectomy; six non-RCC malignant tumors underwent combined and/or intensified treatment; 13 of 15 patients with oncocytoma did not undergo radical nephrectomy (eight underwent observation). Definitive pathology confirmed diagnosis in all cases. Grade concordance was 84%, considering two tiers (high vs low grade). No preoperative clinical variable predicted definitive pathology.Renal tumor biopsy is a safe procedure that leads to radical nephrectomy in most tumors ≥4 cm. Nonetheless, 20% of patients exhibited non-RCC histology. Renal tumor biopsy should be considered in this setting.

The administration of adjuvant chemotherapy for patients with penile squamous cell carcinoma (PSCC) with high-risk features is controversial. In 21 patients who had received adjuvant taxane, cisplatin, and 5-fluorouracil, the expression of p53 in the tumor-positive lymph nodes was the only factor that showed a trend toward poorer survival endpoints. If confirmed, these findings could help in selecting the best candidates for adjuvant chemotherapy. Background: Little is known about the outcomes and prognostic factors of adjuvant chemotherapy for locally advanced penile squamous cell carcinoma after regional lymphadenectomy (LAD). Patients and Methods: We retrospectively reviewed the data from 21 patients who had received taxane, cisplatin, and 5-fluorouracil (TPF, every 3 weeks) in the adjuvant setting at our center. Univariable and multivariable Cox regression analyses were undertaken for disease-free (DFS) and overall survival (OS) of TPF. Results: The patients had received TPF from July 2004 to July 2012 after inguinal (n = 6) or inguinal plus pelvic LAD (n = 15), and the median follow-up was 52 months. Thirteen (61.9%) had pelvic and 5 (23.8%) bilateral inguinal nodal metastases. The median time from LAD to the start of TPF was 5.4 weeks (interquartile range [IQR], 4.1-7.3 weeks). Metastatic tumor tissue from 11 of 19 evaluable patients (57.9%) showed positive immunohistochemistry staining for p53. Univariably, only the expression of p53 showed a trend toward poorer DFS (hazard ratio [HR], 4.14; 95% confidence interval [CI], 0.87-19.68; P = .074) and OS (HR, 4.54; 95% CI, 0.95-21.56; P = .056). The same results were obtained multivariably for DFS (HR, 3.76; 95% CI, 0.78-17.96; P = .096) and OS (HR, 4.29; 95% CI, 0.89-20.57; P = .067). The median DFS was 8.9 months (IQR, 5.9-22.7 months) for p53-expressing patients versus not estimable for non p53-expressing patients (P = .051) and the median OS was 17.2 months (IQR, 12.8-22.7 months) and not estimable, respectively (P = .037). Conclusion: In patients who had received adjuvant TPF for node-positive penile squamous cell carcinoma, p53 IHC expression seemed to be associated with a poorer outcome, and further study is warranted in larger data sets to confirm these findings. This information might be useful to improve the prognostic allocation. (C) 2016 Elsevier Inc. All rights reserved.

Kaposi’s sarcoma (KS) is a rare tumor of vascular origin. It is quite common in HIV patients. It is rarely located on the glans penis, especially in HIV-negative patients (just some tens in the literature). Owing to the rarity of the disease, both the real impact on survival and the most suitable therapy are not known.However, in this 3-patient case series, carbon dioxide laser therapy was effective both for local control and survival. In fact, two late relapses but no disease-related death were recorded. Probably, KS in HIV-negative patients is a slowly progressive disease, not so aggressive as in HIV-positive patients. Laser therapy is easy, fast, and cheap, and may treat the disease radically.If these data are confirmed by further studies, in the foreseeable future, laser therapy may become the gold standard for treating HIV-negative patients affected by penile KS.

Background: Residual retroperitoneal masses in NSGCT need postchemotherapy retroperitoneal lymph-node dissection (PC-RPLND). Open (O) PC-RPLND is a standardized procedure, but morbidity is not negligible and mostly attributable to laparotomy. Laparoscopic (L) PC-RPLND may improve tolerability profile. We evaluated viability, toxicity, and short to medium-term oncologic outcome of L-PC-RPLND following well-defined selection criteria. Patients and Methods: Since February 2011, consecutive patients with a unilateral residual mass (1cm or growing), normalized markers, and limited encasement of inferior vena cava and/or aorta were candidate to unilateral L-PC-RPLND. Surgical performances, histology, hospital stay, complications within 30 days, and survival were recorded. Patients were regularly followed up. Adjuvant chemotherapy was not provided. Results: Sixty-seven patients (stage IIA=14; IIB=41; IIC=7; III=5), representing 29% of all those candidate to PC-RPLND in this time frame, underwent L-PC-RPLND up to August 2015. Median size of the mass was 27mm (interquartile range [IQR] 15-31). Median operative time was 234 minutes (IQR 184-250). Three procedures were converted to open surgery. Mean hospital stay was 3 days (IQR 2-4). Out of three (4.5%), one grade III (lymphocele requiring drainage) complication occurred. Sixty-six (98.5%) patients maintained antegrade ejaculation. Histology revealed teratoma in 76%, fibronecrotic tissue in 21%, and viable cancer in 3% patients. All patients are alive and event free after a median follow-up of 21 months (IQR 10-30). Conclusions: In a referral center, L-PC-RPLND is a transferable option for a proportion of patients with a residual mass. Tolerability is acceptable, and current oncologic outcome is consistent with a safe oncologic profile.

Objective To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor. Patients and Methods In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2-3 or M1 (TNM 2009), and no prior chemotherapy administration. The primary endpoint was the objective response-rate (ORR, according to RECIST v1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. Results From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically-involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR: 32.1%, 80% credibility interval 21.0-43.0%). The median follow-up duration was 19.8 months (IQR: 6.3-25.7); 12-month progression-free survival was 26.2% (95%CI: 13.2-51.9); 12-month overall survival (OS) was 54.9% (95%CI: 36.4-82.8). The median OS of locally-advanced patients was 20 months (IQR: 11.1-not reached). The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in 3 patients (10.7%). Tissue samples from 25 patients were analyzed. Only two patients had HR-HPV-positive tumor. EGFR amplification was found in 4 patients (equally responders and non responders) and it was confirmed in all post-dacomitinib samples. TERT mutations (60%) were found in responders only, PI3K/mTOR pathway gene mutations in 42.9% responders versus 8.3% non responders. Conclusion Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combination chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signaling in relation to dacomitinib activity deserve further studies. This article is protected by copyright. All rights reserved.

Background Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). Patients and methods After transurethral resection of the bladder, T2–T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400 mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively. Results From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9–58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0–69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6–NR), nor was median overall survival (interquartile range: 30.3–NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response ( P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution. Conclusions SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy.

Background Limited information is available regarding the use of androgen receptor (AR) immunohistochemical expression in muscle-invasive or metastatic urothelial carcinoma. We aimed to evaluate the frequency of AR expression by tumor cells (TC), its prognostic role, and its relationship with programmed cell-death ligand 1 (PD-L1) expression in these patients. Patients and Methods From September 2015 to January 2017, we collected tissue from patients who received platinum-based chemotherapy at our center. Immunohistochemistry for AR was performed (1% cutoff of TC). PD-L1 coexpression, by TC or immune cells (1% cutoff), was also analyzed. Molecular analysis of AR gene was performed by sequencing of exons 5 to 8 and by fluorescence in-situ hybridization analysis. Cox models for overall survival (OS), adjusted for stage, visceral metastases, and platinum type, were fitted. Results A total of 110 patients had tumor samples stained. Overall, 48 (43.6%) had AR-expressing TC: 19 (17.3%) had 1%-5% expression, 15 (13.6%) 5%-25% expression, and 14 (12.7%) > 25% expression. Among the latter, 7 had molecularly evaluated tumor tissue: no AR gene mutations or amplifications were found, but polysomy of Xq chromosome was seen. PD-L1 expression by TC and immunohistochemistry concordantly decreased with increasing levels of AR expression by TC. In Cox analyses, AR expression was not associated with OS, both on univariable ( P = .477) and multivariable ( P = .505) analyses. Conclusion AR is frequently expressed in patients with muscle-invasive and advanced urothelial carcinoma, and it does not seem to be prognostic for OS. The AR pathway is worthy of clinical studies to assess its synergistic action with anti–PD-L1 therapy.

Primary epithelioid angiosarcoma of the adrenal gland is extremely rare. Only 37 cases have been reported in the scientific literature.Here we describe the case of a 55-year-old woman affected by metastatic angiosarcoma in the right adrenal gland, who died few days after the histological diagnosis made by fine-needle aspiration (FNA). This is the second case of primary epithelioid angiosarcoma diagnosed by FNA among scientific articles published in English in PubMed. Microscopically, the tumor showed a predominant epithelioid differentiation, thus making the diagnostic process more difficult than usual. Immunohistochemical examination revealed positive reactivity for cytokeratin, CD31, and CD34. The literature shows that epithelioid adrenal angiosarcoma has poor clinical outcome, especially when metastatic at presentation.

Purpose: CD30 is expressed by untreated embryonal carcinoma, supporting the rationale for a targeted approach. However, the reported chemotherapy induced switching off of CD30 noted on immunohistochemistry may affect its therapeutic potential for disease relapse. We evaluated persistent CD30 expression and its prognostic meaning in cases of post-chemotherapy residual disease. Materials and Methods: Paraffin blocks of surgical samples that yielded nonteratomatous viable cells after 1 or more cisplatin based chemotherapy treatments were retrieved and reassessed by 2 pathologists blinded to the study purpose. Multivariable analysis was done for prespecified factors. Results: A total of 49 cases of pure embryonal carcinoma or mixed germ cell tumor from August 1991 to August 2012 had full clinical data and suitable tissue available for analysis. Of the 35 cases (71.4%, 95% CI 56.7-83.4) with preserved CD30 positivity 14 (40.0%) showed residual disease after a median of 1 regimen (IQR 1-2). Five-year overall survival in CD30 positive and negative cases was 37.0% (95% CI 22.1-61.8) and 50.1% (95% CI 27.9-90.0, p 0.078), while after first line treatment it was 23.2% (95% CI 8.6-62.5) and 47.6% (95% CI 18.8-100, p - 0.025), respectively. On multivariable analysis CD30 positivity was a significant prognostic factor for progression-free survival (HR 2.32, 95% CI 1.04-5.19) and overall survival (HR 2.77, 95% CI 1.05-7.29). Conclusions: CD30 was retained even after an intensive pretreatment load, confirming that it is a reliable treatment target. Its expression was associated with a significantly poorer prognosis in multiple relapse/ chemoresistant cases and it was an independent prognostic factor for survival.

Background Different approaches have been described in published studies for carcinoma in situ (CIS) of the glans penis (erythroplasia of Queyrat), including topical chemotherapy or immunotherapy and laser or surgical excision. We evaluated the efficacy of topical imiquimod (IQ) followed by carbon dioxide laser ablation of the lesion. Patients and Methods From 2010 to 2015, 10 patients affected by CIS of the glans were treated by IQ, followed by carbon dioxide laser ablation. For every patient, we performed histologic examination before and after IQ. Local toxicity and adverse effects were recorded. Results After treatment, histologic examination showed no residual tumor in 6 patients (complete response [CR]), stable disease in 2 patients, and progressive disease in 2 patients. Those with a CR had human papillomavirus-related lesions, and they had no experienced relapses after a mean follow-up of 26 months. The 2 patients with progressive disease underwent total penectomy. All patients were alive at the last follow-up examination. All patients experienced a mild local toxicity (burning erythema) but no major adverse effects. Conclusion Local treatment with IQ for glans CIS is effective mainly for human papillomavirus-related lesions. The present study is the first to record the histologic examination findings before and after IQ treatment. The small number of patients, owing to the rarity of this disease, was the main limitation of the present study. IQ must be used carefully, and a close follow-up protocol is mandatory because of the lack of long-term efficacy data.

We addressed the use of perioperative chemotherapy in nodal metastates from penile cancer. Forty-seven N2 to 3M0 patients received perioperative taxane, cisplatin and 5-fluorouracil (T-PF) and 38.3% are disease-free at 22 months. Neoadjuvant T-PF allowed 12 (43%) clinical responsesand4 (14%) complete pathologic remissions among 28 patients, and the 2-year disease-free survival (DFS) was 7.1%. The 2-year DFS was 36.8% after adjuvant T-PF. T-PF is active and is associated with long-term survival after surgery. Chemotherapy must be offered with caution in patients with resectable nodal metastases. Background: The role of chemotherapy in nodal metastases from penile squamous cell carcinoma is not defined. We evaluated the efficacy of a combination of T-PF(a taxane, cisplatin, and 5-fluorouracil) in neoadjuvant and adjuvant settings. Patients and Methods: Since June of 2004, T-PF was administered to stage N2 to 3 patients. With time, neoadjuvant chemotherapy administration prevailed with respect to use in the adjuvant setting. Primary end points were progression-free (PFS) and overall (OS) survival. Secondary objectives were tolerability and activity in the neoadjuvant setting. Nonparametric tests, Kaplan-Meier, and regression analyses were performed. Results: As of October of 2012, 47 consecutive N2 to 3 M0 patients had undergone neoadjuvant (n = 28) or adjuvant (n = 19) T-PF: 18 patients (38.3%) remain disease-free after a median follow-up of 22 months (interquartile range, 17-42 months). The 2-year disease- free survivals were 36.8% (95% confidence interval [CI], 15.2-58.5) versus 7.1% ( 95% CI, 0-16.7) after adjuvant and neoadjuvant therapy, respectively. N3 metastases were associated with a poorer PFS, and bilateral metastases and mutated p53 were associated with a poorer OS. After neoadjuvant treatment, 43% clinical responses and 14% complete pathologic remissions were recorded, but responses were not associated with survival. Neutropenia (25.5%) was the most frequent Grade >= 2 toxicity. Conclusion: The T-PF regimen is well tolerated and compares with other regimens in terms of activity and efficacy in the neoadjuvant setting, and very long survivals have been recorded after adjuvant administration. The role of perioperative treatment in these patients remains controversial. Some caution in administering preemptive treatment in patients with resectable disease is needed. (C) 2015 Elsevier Inc. All rights reserved.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE • To investigate the optimal management and prognostic factors of patients with malignant transformation (MT) in germ-cell tumour (GCT) by re-evaluating Institutional series. PATIENTS AND METHODS • Patients with an MT within GCT have been identified from the institutional database and all slides have been reviewed by the referral pathologist. RESULTS • From June 1982 to October 2009, 48 patients and 13 somatic histologies have been identified. Twelve patients presented with stage I, 12 with stage II and 24 with stage III disease. All stage I patients are alive and disease-free after a median follow up of 88 months (interquartile range 38–103). • Of the 36 metastatic cases, 11 underwent GCT-oriented chemotherapy plus surgery and seven of them are currently disease-free. Three patients underwent MT-chemotherapy, one relapsed and is still under treatment. Overall, 17 patients relapsed (35%) and three of them have been rescued by GCT-chemotherapy. Five-year overall survival was 100% for stage I, 80% (95% CI 40–94) for stage II and 44% (95% CI 19–67) for stage III patients. Stage III disease at MT, incomplete surgical removal and primitive neuroectodermal tumours plus adenocarcinoma histologies were significant adverse prognostic factors for survival. CONCLUSIONS • New insights emerged into the impact of histology and chemotherapy on MT. The development of an adenocarcinoma component as well as the possible efficacy of a GCT-tailored chemotherapy in a multimodal strategy are addressed for the first time, while disease extent at transformation and extent of radical surgery are confirmed as significant prognosticators. • An international web database for registration of all cases of MT worldwide is presented.

564 Background: Despite the overall high cure-rate for patients (pts) with CSI seminoma (sem) regardless of the intervention used, huge discrepancy exists in the number of CT scans that are proposed to pts during FUP period, mainly during active surveillance (AS). The impact of such discrepancy in diagnosing pts with a high-risk relapse was assessed in published literature with a meta-analysis (MA). Methods: We searched for arms of studies of AS or active treatment (AT, adjuvant chemotherapy and radiotherapy) in pts with CSI sem. Meta-analytic techniques were used to pool and compare study level data of AS and AT groups and to study the impact of the number of CT scans (as a continuous variable) during FUP upon the % of pts with CSIII or with IGCCCG intermediate (int) prognosis sem at relapse. Results: 22 studies were analyzed (33 arms, n = 11025 pts). 39.6% had a high-risk sem, 38.8% (n = 4274) underwent AS vs 61.2% (n = 6751) AT. The number of CT scans ≤2y ranged 4-8, and 0-7 for AS and AT groups. Overall, 922 pts experienced a relapse (651 in AS and 271 in AT arms), 73.9%

Objectives Approximately one-third of the metastatic germ cell tumors (GCT) in patients are classified as intermediate-risk metastatic GCT, and available guidelines recommend the same treatment of poor-risk cases. Yet the prognosis of these patients is heterogeneous, and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof of principle for reclassification attempt. Patients and methods Data on consecutive patients with intermediate-risk metastatic GCT and who received treatment at Fondazione INT Milano in the time frame between February 1980 and March 2014 were collected. Cox regression analyses were done, evaluating potential prognostic factors for overall survival (OS, primary end point) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups. Results A total of 224 patients were suitable for the present analysis. Median age was 26 years (interquartile range: 22–31), 11 patients (4.9%) had a retroperitoneal primary tumor, 6 yielded seminomatous histology, 85 (37.9%) had lung metastases, and 58 (25.9%) had bulky (i.e.,≥10 cm) retroperitoneal lymph nodes. Patients received cisplatin, bleomycin, and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23); however, 2 patients received other treatments. Median follow-up was 135 months (interquartile range: 81–223). Globally, 5-year progression-free survival and OS rates were 72.8% (95% CI: 67.1–79.0) and 86.2% (81.7–91.0), respectively. In the multivariable model for OS, elevated alfa fetoprotein (AFP) level was the only significant prognostic factor (hazard ratio = 1.48, 95% CI: 1.12–1.96). The 2 separate prognostic groups with differential OS outcomes were identified based on the cutoff level of 6,200 IU/ml. The 10-year OS rate was 55.6% (95% CI: 36.6–84.3), and it was 86.7% (95% CI: 82.0–91.7) for those with AFP levels more than (n = 19, 8.5%) and less than (n = 205, 91.5%) the cutoff, respectively. Conclusions A small fraction of patients with highly elevated AFP levels have an OS approximating the poor prognostic category, whereas most of them are close to good-risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.

In this retrospective study, patients with poor-prognosis germ cell tumors (GCT) treated from a single referral center demonstrated high survival estimates that were stable through the years. Indeed, the major clinical implication is that using the available prognostic classification of metastatic GCT cannot allow the recognition of patients with a true chemoresistant disease. Moreover, the prognostic effect of treating patients with disseminated disease in referral centers should be further assessed. Background: Survival estimates with first-line treatment for patients with metastatic poor prognosis germ cell tumors (GCT) are still suboptimal in the literature. We conducted a retrospective study to evaluate the outcome of patients referred to our tertiary cancer center. Patients and Methods: A retrospective analysis was conducted on patients who received at least first-line chemotherapy at our center. Distribution of clinical characteristics was evaluated in the periods < 1997, 1997 to 2001, 2001 to 2006, and 2007 to 2013. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariable and multivariable Cox models with prespecified clinical variables were undertaken for PFS and OS. All tests and confidence intervals were 2-sided and set at a P = .05 level of significance. Results: Between 1982 and 2013, 168 patients were identified. The median age was 27 years (inter-quartile range [IQR], 22-34). The presence of liver, bone, or brain metastases trended to greater incidence from 1997 onward (27.5% < 1997 to 55.6% in 2007-2013; chi(2) P = .054). Median follow-up was 102 (IQR, 63-166) months. Global 5-year PFS was 48.5% (95% confidence interval [CI], 41.5-56.8) and OS was 63.2% (95% CI, 56.0-71.2). In multivariable analysis, treatment period was not significantly associated with either PFS (overall P = .229) or OS (overall P = .216). Conclusion: In this single-center series of consecutive poor prognosis GCT we could observe greater PFS and OS than the historical estimates. This observation was independent from the period of treatment. Based on the present results, studies focused on improving the outcome in the sole poor-risk cohort should be discouraged. Results were biased by their retrospective quality.

OBJECTIVE To assess the clinical outcome of testicular sex cord stromal tumors (TSCST) according to management and stage. PATIENTS AND METHODS Clinical and pathologic features, stage, and treatment of patients with TSCST were retrieved from our database. The Kaplan-Meier method estimated the relapse-free survival and cancer-specific survival. RESULTS We identified 67 patients between December 1982 and January 2013: 55 patients (82.1%) had a Leydig cell tumor and 11 patients (16.4%) had a Sertoli cell tumor. Four patients (5.9%) presented with gynecomastia. Forty-eight patients (71.6%) had no pathologic risk factor, and patients 3 had >= 3 risk factors. Testis-sparing surgery was performed in 31 patients (46.3%) and orchiectomy in 36 patients (53.7%). The median tumor diameter was 0.7 cm (interquartile range, 0.6-1.3) and 1.5 cm (interquartile range, 0.9-2.6) in the 2 groups, respectively (P,.007 at Mann-Whitney rank-sum test). The 5-year relapse-free survival was 89.4% (95% confidence interval, 75.9%-95.5%) and cancer-specific survival was 90.3% (95% confidence interval, 72.7%-96.7%), respectively. Metastases were documented in 8 patients (11.9%), 5 relapsing after a median follow-up of 37.4 months. All 3 patients with >= 3 risk factors had metastatic disease. Four of 5 patients with retroperitoneal metastases only were cured by retroperitoneal lymph node dissection (3 patients at presentation and 1 during follow-up); 4 patients undergoing chemotherapy progressed and ultimately died of disease. CONCLUSION Most of the patients with TSCST had a favorable prognosis. Testis-sparing surgery may be feasible and effective in case of small tumors. Few patients had metastatic spread, but only those with nodal metastases may benefit from an early retroperitoneal lymph node dissection. Risk factors associate with disease behavior, but indications to prophylactic intervention remain controversial. (C) 2015 Elsevier Inc.

INTRODUCTION AND OBJECTIVES: To develop a novel postoperative prognostic tool, which attempts to integrate both pathological tumor stage and histopathological factors for prediction of cancer-specific mortality (CSM) for SCCP. METHODS: Patients with SCCP treated with inguinal lymph node dissection (ILND) or sentinel node biopsy at a single institution were used for nomogram development and internal validation (n1⁄4434), while a second cohort was used for external validation (n1⁄4338) Multivariable Cox proportional hazards were used to examine the prognostic ability of patient age, a modified tumor staging that distinguishes between spongiosum and cavernosum body ingrowth tumors, a modified nodal staging that integrates information on presence/absence of lymph node metastasis, extent of inguinal metastases, pelvic nodal involvement, and extranodal involvement, and tumor grade. Model performance was quantified using measures of discrimination and calibration. RESULTS: Overall, 36% of patients had positive lymph node metastases (n1⁄4156). In univariable analyses, the modified tumor and nodal staging systems were statistically significantly associated with CSM, and remained in the final model with a discrimination of 89% within internal validation, and 95% within external validation. Calibration was nearly perfect. CONCLUSIONS: The newly developed model integrates important prognostic factors, which existing models do not consider. Its performance was highly accurate using measures of discrimination and calibration.

MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) chemotherapy (classic or dose-dense) is one of the current choices of therapy for locally advanced and metastatic urothelial cancer. The poor safety profile and not significantly greater efficacy as compared with cisplatin/gemcitabine are major issues. The authors analyzed the outcomes of a series of modified MVAC schedules in these patients, all treated at their center over a 26-year period. A fairly good tolerability, coupled with efficacy seemingly equal to that of the original MVAC, was obtained. Background: The classic MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) regimen was the first recognized option for untreated patients with locally advanced or metastatic urothelial cancer (UC). Modifying MVAC by reducing side effects may have the potential to improve efficacy. Patients and Methods: Changes to classic MVAC were provided at the authors' institution: (1) deletion of day 22 and administration of 25 mg/m(2) cisplatin on days 2 to 5 (modified [m] MVAC); (2) deletion of day 22 only (simplified [s] MVAC1); and (3) deletion of days 15 and 22 in a 3-week schedule (sMVAC2). A total of 4 to 6 cycles were provided. Multivariate analysis was undertaken for recognized clinical variables. Results: For the period from September 1986 to May 2012, 157 patients were identified (25 with mMVAC, 72 with sMVAC1, and 60 with sMVAC2). Overall, 43.9% had a Memorial Sloan-Kettering Cancer Center score of 1 or 2, with differences across series (P = .002). Altogether, 65.8% attained a complete (19.1%) or partial response (46.7%), and 24.3% a stable disease, with no difference across regimens. After a median follow-up of 87 months (interquartile range, 37-161), median progression-free survival was 10.2 months (95% CI, 8.4-10.8), and median overall survival (OS) was 19.5 months (95% CI, 16.3-24.1). Responses were mainly seen in nodal metastases or soft tissue relapse (odds ratio, 2.48; 95% CI, 1.12-5.54). Only visceral (hazard ratio [HR], 2.42; 95% CI, 1.37-4.30) and nodal metastases/local relapse (HR, 1.70; 95% CI, 1.07-2.69) were independently associated with OS. Grade 3 or 4 toxicities were similar across regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. Two treatment-related deaths occurred. Conclusion: Simplifying MVAC may result in improved efficacy and reduced toxicity. The combined results of the original and modified MVAC regimens encourage a reappraisal of the frontline management of advanced UC.

Fluorine-18 fluorodeoxyglucose positron emission tomography is increasingly used by many centers for staging and response assessment of metastatic transitional cell carcinoma. We prospectively evaluated 31 patients undergoing metabolic restaging after only 2 cycles of first-line chemotherapy (PET2). Early metabolic response was associated with patient outcome. The aim was to provide a proof of principle for a risk-adapted approach based on PET2 that may guide new trial design for early-recognized unresponsive patients. Background: The prognostic impact of early metabolic response by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) after 2 cycles of first-line chemotherapy is still unrecognized in metastatic transitional cell carcinoma (TCC). Patients and Methods: Patients with metastatic TCC receiving the modified combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), according to institutional protocol, underwent computed tomography (CT) and FDG-PET imaging at baseline, a restaging with PET imaging after 2 cycles only (PET2), and a CT (+/- FDG-PET) scan at the end of treatment and during follow-up. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method; univariate (UVA) and multivariate (MVA) Cox models were fitted. Prespecified variables were the presence of visceral metastases, nodal or soft tissue disease, and early PET response. Results: In the period from May 2010 to October 2012, 31 patients with Eastern Cooperative Oncology Group performance status 0 received the modified MVAC regimen every 3 weeks. In all, 6 patients (19.3%) had a complete response (CR) and 17 (54.8%) a partial metabolic response (PR), 4 had stable disease (SD), and 4 progressed. PET2 responders had a median PFS of 8 months (95 % CI, 7-11 mo) compared with 3 months (95 % CI, 2-5 mo) of patients without response (P = .024). They also had a significant benefit in 8-month PFS (P < .001 via Klein test) and 15-month OS (P = .016). PET2 response was significant for PFS in both UVA and MVA Cox models (P = .027 and P = .023, respectively). Conclusion: PET response after 2 cycles of first-line chemotherapy, compared with detection by early CT, was associated with longer PFS and OS in advanced TCC and warrants further investigation in the field. (C) 2014 Elsevier Inc. All rights reserved.

Purpose: We determined predictors of pelvic lymph node metastases in patients with penile cancer. Materials and Methods: We retrieved a total of 188 node positive inguinal groins from 142 patients treated for penile cancer. Logistic regression models were fitted to test for predictors of pelvic lymph node metastases. The minimum p value method was used to determine the most significant cutoff values of each predictor. Results: Pelvic lymph node metastases were observed in 45 cases (31.7%). The 5-year cancer specific survival rate was 71.0% vs 33.2% in patients with inguinal vs pelvic lymph node metastases. The most significant cutoff values were 3 inguinal lymph node metastases and a metastasis diameter of 30 mm. According to univariable logistic regression models the number of inguinal metastases (OR 1.92, p

Objective To evaluate the association between lymph node ratio (LNR) and cancer-specific survival (CSS) in a population of patients with penile cancer and lymph node metastases (LNM). Patients and Methods We evaluated 81 patients with pathologically determined LNM who were surgically treated at our institution between 2000 and 2012. We considered LNR both as a continuously coded and as a categorically coded variable. The minimum-P-value approach was used to determine the most significant LNR threshold. The Kaplan–Meier method was used to determine CSS rates, and univariable and multivariable Cox regression models were fitted to test the predictors of CSS. Results The median (interquartile range [IQR]) numbers of positive and removed lymph nodes were 2 (1–4) and 22 (13–30), respectively. The median (IQR) LNR was 10.3 (6.3–16.6)% and the most significant LNR threshold was 22%. The median (IQR) follow-up was 26 (16–62) months. Overall, the 5-year CSS rate was 50.5%. After stratification according to LNR, 5-year CSS rates were 65.2% vs 9.6% in patients with LNR < 22% vs LNR ≥ 22%, respectively (P < 0.001). In multivariable Cox regression models, after adjusting for several established prognostic factors, LNR was as independent predictor of CSS (P≤0.012). Finally, LNR significantly improved the accuracy of multivariable Cox regression models by 4.9–10.5%. Conclusions Although further investigations are needed to evaluate the relationship between tumour burden and treatment intensity, LNR may represent a powerful predictor of CSS in patients with penile cancer and pathologically determined LNM.

A low but invariable proportion of patients with advanced germ cell tumors still fail to be cured by first-line chemotherapy, and the number of life years lost is one of the highest among solid tumors. For patients with chemoresistant disease, the readministration of cisplatin, combined with paclitaxel and gemcitabine (TPG), was tolerable and provided long-term remissions in otherwise incurable patients. Background: Rescue of patients who fail to be cured after 2 or 3 chemotherapy combinations (including high-dose chemotherapy [HDCT]) or whose disease is refractory to cisplatin is still an unmet need. We assessed the efficacy of a triple-combination chemotherapy in the salvage setting, beyond second-line regimens. Patients and Methods: We retrospectively reviewed institutional data on consecutive patients who received paclitaxel 80 mg/m(2) intravenously (IV), cisplatin 50 mg/m(2) IV, and gemcitabine 800 mg/m(2) IV on days 1 and 8 every 3 weeks for a maximum of 8 administrations, followed by surgery. Response, survival (progression-free survival [PFS] and overall survival [OS]), and safety/toxicity outcomes were the end points. The Kaplan-Meier method was used for survival estimates, and multiple Cox regression models were used to analyze the prognostic factors. Results: Seventy-five patients were treated from April 1999 to July 2011. Eight complete responses (CR, 10.7%), 29 partial responses with normal markers (PRm(-), 38.7%), and 13 cases of incomplete response/stable disease were recorded, for a major response rate (CR + PRm(-)) of 49%. Thirty-three patients (44%) underwent surgery, which was radical in 14 cases (42.4%). Two-year PFS was 14.8% (95% confidence interval [CI], 8.5%-25.8%), whereas 2-year OS was 29.5% (95% CI, 20.3%-42.7%). Five-year OS in disease-free patients (no evidence of disease) was 60.3% (95% CI, 42.2%-86.2%), and median OS between patients with and without evidence of disease was significantly different (71 [interquartile range {IQR}, 14-116] vs. 12.5 [IQR, 8-19] months with a 6-month landmark analysis; P=.0019). Conclusion: TPG is an effective combination, and best results were achieved if a radical clearance of residual disease could be accomplished. A randomized comparison with dose-intensified regimens is advisable. (C) 2014 Elsevier Inc. All rights reserved.

Neoadjuvant systemic cisplatin, methotrexate and vinblastine chemotherapy has been used in the treatment of 69 patients with advanced bladder cancer (stages T2-T4 N+/N0 M0). Sixty patients were evaluable for response at a median follow-up of 48 months. Preoperative resection of the tumor was purposely avoided in order to keep a marker lesion. After planned radical cystectomy, pathological complete responses (pCRs) and partial responses (pPRs) were documented in 5 (8.3%) and 29 cases (43.4%), respectively. These patients had a 5-year disease-free survival rate of 80%, which was statistically superior (p = 0.0013) to 35% for the remaining nonresponding patients. One patient (20%) with a pCR died of systemic disease after 14 months, while the remaining 4 patients (80%) are alive and free of disease after a median follow-up of 57 months. A higher percentage of pCRs and pPRs was observed in the group of patients with stage T3b-T4 tumor (pCR 11%, pPR 63%) in contrast to the patients with stage T2-T3a disease (pCR 4.5%, pPR 45.5%), even if no significant difference in the 5-year survival rate was observed between the 2 groups. Patients with a G2 tumor before chemotherapy survived longer (5-year survival rate of 78%) than those with G3 disease (5-year survival rate of 61%), but no significant difference was achieved.